Depression is highly prevalent among patients with chronic obstructive pulmonary disease (COPD) and is associated with adverse clinical outcomes. The overall goal of this proposal is to examine the impact of inflammation and genetic risk factors on depression in patients with severe COPD, and to assess the combined effects of inflammation, genetics, and depression on changes in functional outcomes. There is increasing evidence that COPD is associated with systemic inflammation that impacts other organ systems. High levels of systemic inflammatory markers have also been linked to increased risk of depression in both healthy and chronically ill populations. The neurotransmitter serotonin which is involved in the pathophysiology of affective disorders is regulated by the serotonin transporter (SERT) that controls reuptake of serotonin at brain synapses. Recent studies report that SERT polymorphisms are associated with depression, suggesting that variants of this gene may be important in determining whether patients with COPD will develop depression during the course of their disease. The preliminary data linking SERT polymorphisms with depression and data suggesting a relationship between inflammation, depression and COPD strongly argue for a large scale prospective study to critically test these relationships. Therefore, the aims of this prospective study of patients with moderate to very severe COPD are to: 1) Examine the relationship between SERT polymorphisms with depression; 2) Examine the bi-directional longitudinal relationship between markers of systemic inflammation (CRP, IL-6, and TNF-1) and depressive symptoms in COPD, and explore the role of exacerbations and SERT genotype in this relationship; and 3) Determine the effect of depression, inflammation, and SERT genotype on decline in functional outcomes (six minute walk test distance, physical activity measured with accelerometers, dyspnea severity, and health related quality of life) in COPD over 2 years. Patients with COPD GOLD Stages II-IV (n=350) will be recruited from two clinical sites over 30 months. Assessments at baseline, year 1 and year 2 will include: blood samples for genotyping (5-HTTLPR and STin2 VNTR) and cytokine assays, spirometry, assessment of depression, functional capacity (six minute walk test), performance (physical activity derived from accelerometry), dyspnea, and health related quality of life (HRQL). We will use advanced longitudinal statistical techniques, structural equations modeling and latent growth models, to assess the dynamics of change in depression, inflammation, and functional status as posited by our models as these processes unfold over time. Public Health Relevance: COPD is expected to be the third leading cause of death by 2020. Understanding the impact of genetics and inflammation on depression as well as the relative influence of these factors on the decline in functional outcomes will inform the development of more tailored medical and behavioral interventions to improve depression and functional outcomes in patients with COPD. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death in the United States, is characterized by chronic, progressive worsening shortness-of-breath, cough and sputum production, and 25- 50% of patients will develop depressive symptoms. The overall goal of this proposal is to examine the impact of inflammation and genetic risk factors on depression in patients with moderate to severe COPD, and to assess the combined effects of inflammation, genetics, and depression on changes in functional outcomes. Understanding these relationships will in inform the development of more tailored medical and behavioral interventions to improve depression and functional outcomes in patients with COPD.